Neurotransmitters: Amines and Histamines

• Neurotransmitters include Acetylcholine (ACH), which comprises an acetyl and choline molecule

Biogenic Amines

• These include catecholamines and indolamines

Catecholamines

• Dopamine (DA) is found in the basal nuclei and limbic system
• Norepinephrine (NE), also known as Noradrenaline
• Epinephrine (E), also known as Adrenaline
• Dopamine in the limbic system affects motivation, drive, and reward mechanisms
• Cocaine enhances dopamine receptors

Indolamines

• Serotonin (5-HT) has 16 receptor subtypes and is located in the limbic system
• Serotonin impacts affective disorders like depression
• Serotonin levels can be increased using Selective Serotonin Reuptake Inhibitors (SSRIs)
• Melatonin falls under the indolamines category

Histamines

• Histamines have roles in inflammation and act as neurotransmitters
• Histamines in the posterior hypothalamus modulate sleep
• Destruction of histamine-releasing neurons can lead to the inability to stay awake
• Anti-histamines, specifically H1 receptor blockers, help induce sleep

Amino Acids

• Glutamate and Aspartate are the primary excitatory neurotransmitters in the Central Nervous System (CNS)

Glutamate

• AMPA receptors are named for agonist gamma Amino 3 hydroxyl 5 Methylisoxazole-4 Proprionic Acid
• NMDA receptors are N-methyl-D-aspartate receptors
• NMDA receptors activation allows Na+, K+, and Ca+2 passage into the cell

NMDA Channels

• NMDA channels are blocked by a gate made of Mg+2 at resting potential
• Glutamate needs to bind and be already depolarized for the channels to be active
• Ca+2 then enters and initiates signal transduction pathways
• This process makes the cell more sensitive to glutamate, causing potentiation which is related to memory and learning
• Psychoactive substances like phencyclidine (PCP), alcohol (ethanol), dextromethorphan (DXM), ketamine, and nitrous oxide affect the activity of NMDA receptors
• Memory formation involves both AMPA and NMDA receptors
• AMPA receptors allow Na+ to flow into the postsynaptic cell, resulting in depolarization
• NMDARs are permeable to both Na+ and Ca+2
• The influx of Ca+2 into the NMDAR activates biochemical cascades, triggering the up-regulation of AMPARs and increases the sensitivity of glutamate, strengthening synapses

GABA

• GABA is the main inhibitory neurotransmitter in the brain (CNS).
• GABA, which is Gamma-amino butyric acid, binds to receptors associated with Cl- channels
• Too little GABA causes too many neuronal signals, potentially leading to mood disorders, epilepsy, and seizures
• Anti-anxiety drugs like benzodiazepines increase GABA production by activating GABAnergic neurons
• Tetanus toxin inhibits the release of GABA in the spinal cord

Glycine

• Glycine functions as an inhibitory neurotransmitter specifically in the spinal cord (CNS)
• It alters Cl- permeability of afferent pathways, which aids to inhibit transmission
• Glycine filters transmission of sensations and modulates sensory input in the spinal cord and thalamus shutting off sensation
• Strychnine, a poison, blocks glycine receptors, leading to excessive excitement

Neuropeptides

• Neuropeptides are composed of two or more amino acids

Substance P

• Substance P is found in high concentrations in spinal cord and hypothalamus
• Substance P is secreted by neurons that transmit pain and temperature
• Nociceptors transduce tissue damage

Pain Transduction

• High concentrations are in spinal cord and hypothalamus; found in and secreted by neurons that transmit pain/temperature (nociceptors ->> transduce tissue damage)
• Opioid receptors mediate presynaptic effects by decreasing Ca influx and transmitter release
• Opioid receptors mediate postsynaptic effects by increasing K conductance and hyperpolarization

Capsaicin

• Capsaicin, found in hot peppers, causes a "burn" sensation on the tongue, lips, and eyes
• Capsaicin binds to the TRPV1 protein on pain and heat-sensing neurons
• TRPV1 is a heat activated/damage activated calcium channel that opens between 37-45 °C
• Capsaicin causes the TRPV1 channel to open below 37 °C
• This results in a chemical mimicry of a burning sensation
• Depleting Substance P can block pain
• Chronic exposure to capsaicin depletes Substance P in neurons, reducing pain and blocking neurogenic inflammation. If capsaicin is removed, the neurons recover

Opioids

• Opioids include endorphins, enkephalins, and dynorphins
• Opioids bind to the same receptors as opium and morphine
• They offer pain relief and act as powerful analgesics
• Opioid examples include heroin, morphine, fentanyl, oxycodone (OxyContin®), hydrocodone (Vicodin®), and codeine
• In the PNS, mu-opioid receptors are in afferent neurons, peripheral sensory fibers, and dorsal root ganglia.
• When bound, they inhibit the release of substance P
• In the CNS, beta-endorphins bind mu-opioid receptors at presynaptic nerve terminals
• Instead of inhibiting substance P, they inhibit the release of GABA, resulting in more dopamine production
• Dopamine is associated with pleasure
• In the CNS, mu-opioid receptors are most abundant in descending pain control circuits including the amygdala

Cannabinoids

• Cannabinoids bind to CB1 receptors and inhibit Ca+2 entry into the axonal terminal hence inhibiting GABA secretion and Glutamate secretion
• Cannabinoids that are plant-derived include Tetrahydrocannabinol (THC)
• Cannabinoids that are endogeneous include Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG)
• CB1 receptors modify the activity of intracellular enzymes like cAMP
• Reduced cAMP means there is less protein kinase A and affects K and Ca channels, reducing neurotransmitter release
• General excitability of the brain's neural networks is then reduced

Cannabinoid Receptor Function

• CB1 receptors modify the activity of several intracellular enzymes, including cAMP, and their role depends on the specific cell type and brain region where they are expressed
• In GABAergic neurons, activation of CB1R can decrease coping strategies, potentially reducing activity of GABAergic interneurons in the basolateral amygdala
• In the reward circuit, cannabinoid increases dopamine release
• Dopaminergic neurons in this circuit do not have CB1 receptors, but are normally inhibited by GABAergic neurons that do. Cannabis removes this inhibition, activating dopamine neurons

Pathologies

• Neuritis: Inflammation of neurons due to traumatic event, pathology, or drugs
• Pain from neuritis: Neuralgia
• Sciatica: Inflammation of the sciatic nerve
• Tic douloureux: Trigeminal (CN V) neuralgia
• Bell's Palsy: Paralysis of CN VII facial nerve
• Shingles: Chicken pox virus, causes immunity but the virus is not completely destroyed
• Shingles travels back from some dermatome, lays dormant, and takes root in the dorsal root ganglion If the immune system weakens, the virus becomes active, traveling over sensory nerves causing excruciating pain Cerebral Palsy: Damages to the motor parts of the brain, usually early in childhood due to O2 deprivation Damage during birth or trauma to the head can cause Cerebral Palsy This condition does not affect the afferent or integration parts
• Tumors; neuroma (tumor of the nervous system); glioma (tumor of glial cells and most interferes with neuron function)
• Multiple Neurofibromatosis: Genetic, numerous fibrous neuromas, associated with Schwann cells

Other Pathologies

• Cerebral Vascular Accident (CVA or stroke): Blockage or rupture of blood vessel to the brain, a leading cause of death
• Transient Ischemic Attack (TIA): A transient ischemic attack is the least severe
• Seizure Disorder: 2nd most common brain disorder- sudden uncontrolled bursts of abnormal neuronal activity and jerky involuntary movement
• Meningitis: Inflammation of meninges, can be bacterial, resulting in stiff neck, fever, seizures, with a 20% mortality rate
• Encephalitis: Inflammation of brain tissue itself, virally mediated causing a more severe and higher rate of mortality than meningitis
• Alzheimer's Disease: Age-related irreversible loss of neurons and loss of intellectual abilities, affecting 4 million in the US where Plaques form around the brain, protein (-beta-amyloid between cells) and tangles (tau – inside cells)
• Alzheimer's Accounts for 1/3 of cases of age-related dementia, It affects 10% of people aged 60-65 and 35-45% of people over 85